A review of the development of solid phase peptide synthesis is available in "Peptide Synthesis", 2nd Ed., M. Bodanszky et al., John Wiley (1976) Chapter Seven, or "The Peptides: Analysis, Synthesis, Biology", Gross, Meienhoffer, Academic Press (1979) Vol. 2, Chapter 1. Originally, chloromethylation of a styrene-divinylbenzene copolymer using monochloromethyl ether in the presence of tin chloride gave a chloromethylphenyl resin which was initially attached to a N-protected amino acid by an ester linkage.
Later for the synthesis of peptide amides, the resin was acylated using a benzoyl halide in a Friedel-Krafts reaction to give benzoylphenyl resin which was converted to a benzhydrylamine resin by reductive amination such as using a Leuckart reaction [J. Hruby et al., J. Org. Chem., 42 3552 (1977), or P. Pietta et al., J. Org. Chem. 39 44 (1974)]. This reaction, or variations of it, has proved useful to the peptide chemist. p-Methylbenzhydrylamine resins, G. R. Matsueda et al., "Peptides", Vol. 2, 45 (1981); p-methoxybenzhydrylamine resins, R. Orlowski et al., J. Org. Chem. 41 3701 (1976); p-nitrobenzhydrylamine resins, R. Colombo, J.C.S. Chem. Comm. 1981 1012; or o,p-dimethoxybenzhydrylamine resin have been used to efforts to improve the procedure. These resins were prepared to increase the lability of the peptide-resin bond, not to improve the overall procedure. Most were made by the reaction sequence described above.
Only the Leuckart reduction method yielded a usable product, M. Christensen et al., Acta Chemica Scandinavica B 35 (1981) 573 or R. Walter et al., J. Org. Chem. 41 3701 (1974). This method has a number of disadvantages, such as poor purity which is especially due to admixture of unreactive keto material, high cost, low and variable yields, long time of chemical throughput and lack of predetermination of the degree of polystyrene substitution.
The present invention contributes to the solution of this prior art problem.